A major challenge of the MMHCC is to develop genetically defined mouse models that accurately reflect the human disease. Our group has developed two different mouse models of prostate cancer derived from two distinct molecular events associated with human prostate cancer - amplification of c-Myc and loss of PTEN. Both models progress from prostatic intraepithelial neoplasia (PIN) to invasive adenocarcinoma and metastasis. Preliminary expression profiling experiments have identified candidate secondary genetic events known to be associated with human prostate cancer. Some are shared across both models, whereas others are pathway - specific. The goal of our renewal application is to fully characterize disease initiation and progression in these models using global gene expression tools, followed by intensive comparisons to human prostate cancer datasets collected at the Dana Farber Cancer Institute. The highest priority genes will undergo functional evaluation using prostate reconstitution assays and additional mouse crosses. The models will also be used to study mechanisms of response and resistance to current clinical prostate cancer therapies (anti-androgens) and to novel signal transduction inhibitor therapy (against mTOR), based on our expertise with these inhibitors in xenograft models. Finally, our models provide tools to define the cell of origin in prostate cancer, so that additional cell-type specific therapy might be developed. Although focused on prostate cancer, the studies outlined here will be broadly relevant to cancers associated with Myc or PTEN dysregulation, and our strategy for parallel analysis of mouse and human datasets can be generalized more broadly to other cancer models.